Global Evidence for the Use of Calcium for PE/E Prevention Jeffrey Michael Smith, MD, MPH Jhpiego / Johns Hopkins University Maternal Health Team Leader MCHIP Kathmandu, 9 December 2013

2 Pre-eclampsia Quick reminder:  Blood pressure ≥ 140 / 90  Proteinuria  In a pregnant woman ≥ 20 weeks or greater, with no pre-pregnancy history of pre-eclampsia

Dietary modification program in Sydney RHJ Hamlin Lancet 1952

Experience in Ethiopia Hamlin RHJ. Prevention of pre-eclampsia. Lancet 1962;1:

Pre-eclampsia and dietary calcium  Low incidence of pre-eclampsia noted in Guatemala (Belizan 1980)  Postulated due to high calcium diets Belizan JM, Villar J. The relationship between calcium intake and edema, proteinuria, and hypertension-gestosis: an hypothesis. American Journal of Clinical Nutrition 1980;33:

Calcium supplementation among low calcium intake women: WHO randomized trial Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali M, Zavaleta N, Purwar M, Hofmeyr GJ, thi Nhu Ngoc N, Campódonico L, Landoulsi S, Carroli G, Lindheimer M et al. Am J Obstet Gynecol 2006;194: ↓ Revised Systematic Review: Hofmeyr GJ, Lawrie TA, Atallah ÁN, Duley L. Cochrane Database of Syst Reviews 2010

Calcium vs Placebo: Pre-eclampsia

Calcium vs Placebo: Proteinuria

Calcium vs Placebo: Eclampsia

Calcium vs Placebo: Maternal Death

Calcium vs Placebo: Maternal death / severe morbidity

Calcium vs Placebo: Preterm birth

Calcium and pre-eclampsia  Epidemiological association of dietary calcium deficiency with pre-eclampsia / eclampsia  Calcium supplementation reduces:  Pre-eclampsia by 64% (but only 8% in WHO trial)  Severe morbidity by 20%  Preterm birth by 10% (borderline significance)  Increases HELLP syndrome

Hypothesis: Calcium supplementation in 2 nd half of pregnancy:  ↓ blood pressure (↓ vascular tone)  ↓ serious complications related to hypertension  No effect on ‘underlying pre-eclampsia process’  ↓ early deliveries in Ca group → more women went on to develop HELLP syndrome  To prevent underlying pre-eclampsia process may need adequate calcium from before pregnancy Hofmeyr G, Duley L, Atallah A.Hofmeyr G, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic review and commentary. BJOG. 2007; 114:

Based on this evidence:  World Health Organization recommends (2011) calcium supplementation with 1.5 to 2g calcium daily to pregnant women with low dietary calcium intake  BUT:  Large dose difficult to implement  May be unnecessarily large, or even harmful

Daily intake of calcium per capita in developing/developed countries (FAO, 1990) REGIONCALCIUM (mg) World472 Developed countries860 Developing countries346 Africa 363 Latin America499 Near East498 Far East352 Others402 About 500 mg

 Cochrane methodology  Primary inclusion criteria:  Calcium supplementation <1g without co-supplements  Secure allocation concealment (low risk of bias)  Double blinding with placebo  If the above criteria failed to produce adequate data, we planned to include:  quasi-randomized trials  trials without placebo control  trials of multiple supplements,  with appropriate caution in the interpretation

Cochrane review: Low dose calcium

Results  All trials used 500mg daily  Consistent 60% reduction in pre-eclampsia across all 9 trials (2234 women)  Significant reduction for all high quality trials; and all trials of calcium alone  An unexpected finding in one high quality trial of calcium plus antioxidants commencing at 8-12 weeks of pregnancy was a trend to reduced miscarriage (1/29 versus 8/31, RR 0.06, 95% CI 0.00 to 1.04).

Conclusions  Available evidence supports the probable effectiveness of low-dose calcium supplementation  Low quality of evidence requires further research  If the WHO recommendation of 1.5 to 2g calcium daily is not achievable, it is reasonable to use a lower dosage (eg 500mg daily)

The Calcium and Pre-eclampsia (CAP) study (WHO Study A65750)  Randomized trial: calcium 500mg daily vs placebo commencing before conception till 20 weeks  All women receive routine calcium in second half of pregnancy  Participants: women with previous pre-eclampsia who intend to conceive  If effective, next step will be food fortification  Analysis plan includes measuring effect on conception and miscarriage.

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